3D Organoids Reveal a Critical Role for Microenvironment in Polycystic Kidney Disease
Kidney organoids are three-dimensional units with proximal tubules, distal tubules, and podocytes in patterned segments, recapitulating the architectural subunit of the kidney. Using CRISPR-Cas gene editing, we have further generated kidney organoids with loss-of-function mutations in genes associated with polycystic kidney disease (PKD), which form cysts from kidney tubules similar to the human disease. When PKD organoids are grown in the absence of adherent cues, the rate of cystogenesis is greatly increased, and the organoids expand 4,000-fold in size, generating cysts that can readily be seen in by eye. Screening of organoids in high throughput formats further identifies a new role for non-muscle myosin in this disease, which may facilitate attachments between tubular cells and their surroundings. These findings reveal a critical role for microenvironment in human PKD, and raise new possibilities for understanding disease from the cellular to the organoid scale.